A novel missense variant in PNLDC1 associated with nonobstructive azoospermia
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Date
2024-08
Journal Title
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Publisher
The Indian Academy of Sciences
Abstract
The most severe type of male infertility is nonobstructive azoospermia (NOA), where there is no sperm in the ejaculate due to failure of spermatogenesis. The predictable frequency of NOA in the general population is one in 100 men. Genetic studies have recognized dozens of NOA genes. Most NOA aetiologies remain idiopathic. Monogenic mutations can be a reason for a part of idiopathic NOA cases. To address this, we studied the pedigree of a consanguineous family with three NOAs by a family-based exome sequencing. Our goal was to pinpoint the genetic variants responsible for idiopathic NOA to aid future clinical genetic diagnostics and treatment strategies. Bioin- formatics analysis followed by Sanger sequencing revealed that NOA patients were homozygous for a rare novel missense variant in PNLDC1 (NM_173516:exon9:c.710G[A;p.Gly237Asp). In silico, single-cell RNA sequencing data analysis and protein modelling demonstrated that PNLDC1, Gly237Asp resided in the conserved region of the CAF1 domain which could lead to local instability in the structure and alteration of protein phosphorylation site. We conclude that the novel missense PNLDC1 variant may affect meiosis and spermatogenesis, leading to NOA and the genetic cause of this idiopathic NOA family. Our result helps genetic counselling for idiopathic NOA cases and provides the occasion for more efficient diagnosis in the clinical setting.
Description
Keywords
whole-exome sequencing, transposable elements, spermatogenic failure diseases, CAF1 domain.
Citation
RAHIMIAN MOUNESS, ASKARI MASOMEH, SALEHI NAJMEH, JAAFARINIA MOJTABA, FOROUZANFAR MOHSEN, ALMADANI NAVID, RICCIO ANDREA, TOTONCHI MEHDI . A novel missense variant in PNLDC1 associated with nonobstructive azoospermia. Journal of Genetics . 2024 Aug; 103: 1-10